Mechanisms controlling liver regeneration and differentiation are studied in this laboratory. Our approach has been to develop a functional primary fetal rat hepatocyte monolayer culture system. Serum and tissue factors are isolated and tested for stimulatory and/or inhibitory effects upon in vitro initiation of DNA synthesis and mitosis. Relationships between these factors and in vivo hepatoproliferative alterations then are determined with different animal models including partial hepatectomy, hormone infusion, nutritional deprivation, neonatal development, and selected mutant strains. A complex pictue of integrated endocrine control along with growth-associated hepatic plasma membrane changes ("glucagon resistance") has emerged. Hepatocyte GO-populations may be heterogeneous, the physical basis of which could arise from different steady-state equilibrium interactions with cell receptors and hormones. In vivo physical conditions which putatively generate heterogeneous GO-states are suggested to result from positional information gradients radiating from the portal triad towards the central vein. This physiological mechanism could be of survival value during liver regeneration. The "specificity" of regeneration may be relative; different environmental pretreatments appear to "select" the set of blood-borne factors which "initiate" proliferation. Recent work has implicated non-peptidic dialyzable brain factors in proliferative control. This observation and its relationship to hepatic function and neurogenic involvement during proliferative processes is under intensive investigation. BIBLIOGRAPHIC REFERENCES: Leffert, H.L. Hepatocellular Growth Control. In Workship on Rat Liver Pathology (P. Newberne and W. Butler, eds.), Elsevier, North Holland, Amsterdam (1975). Leffert, H., Alexander, N.M., Faloona, G., Rubalcava, B., and Unger, R. Specific Endocrine and Hormonal Receptor Changes Associated with Liver Regeneration in Adult Rats. Proc. Nat. Acad. Sci. USA, 72, 4033-4036 (1975 .